Recipient LAG3 deficiency results in antibody-mediated rejection of mouse renal allografts

Abstract

AbstractLymphocyte activation gene-3 (LAG3) is a coinhibitory receptor expressed by a wide range of immune cells. While LAG3 is predominantly studied in T cells, its functions in humoral immune responses remain poorly characterized. The goal of this study was to test the role of recipient LAG3 in a mouse model of renal allograft rejection. Compared to WT animals, naïve B6.LAG3-/-mice have increased splenic cellularity and higher frequencies of CD44himemory T cells, CXCR5hifollicular T cells, and B220+CD138+plasma cells yet do not develop spontaneous autoimmunity. Furthermore, naïve B6.LAG3-/-(H-2Db) mice have increased frequencies of memory T cells recognizing H-2Dd, H-2Ds, H-2Dqand H-2Dkalloantigens. In addition, naïve non-transplanted B6.LAG3-/-mice have elevated levels of serum IgG reactive to allogenic class I and class II MHC molecules. Whereas 4/4 B6.WT recipients spontaneously accept fully MHC-mismatched C3H (H-2k) renal allografts for longer than 60 d, recipient LAG3 deficiency led to rapid allograft rejection and elevated serum creatinine levels. Graft histology at rejection revealed minimal T cell infiltration, diffuse C4d staining, atrophic peritubular capillaries, endothelial swelling and edema characteristic of antibody mediated rejection (AMR). Compared to WT, LAG3-/-recipients had elevated frequencies of anti-donor IFNγ producing T cells and increased levels of anti-donor MHC antibodies. Recipient CD8+T cell depletion did not alter the rejection kinetics in LAG3-/-recipients, while B cell depletion significantly extended C3H kidney allograft survival. Conditional knockout mice were used to determine the importance of LAG3 expression by T and B lymphocytes. The absence of LAG3 on either T or B lymphocytes had no impact on graft rejection with both groups accepting kidney allografts for longer than 30 days, suggesting that LAG3 expression on either T or B cells is sufficient to regulate immune responses to kidney allografts. These results suggest that LAG3 is a regulator of both T and B cell responses to kidney allografts and is an attractive potential therapeutic target for AMR prevention and treatment.